Objective To compare short-term outcomes between two- vs. three courses of neoadjuvant chemotherapy (NAC) to clarify the optimal treatment for esophageal squamous cell cancer (ESCC) in a multicenter, randomized, phase II trial. Background An optimal number of NAC cycles remains to be established for locally advanced ESCC. Methods Patients with locally advanced ESCC were randomly assigned to either two ( N  = 91) or three ( N  = 89) courses of DCF (70 mg/m 2 intravenous docetaxel and 70 mg/m 2 intravenous cisplatin on day 1, and a continuous 700 mg/m 2 fluorouracil infusion for 5 days) every 3 weeks followed by surgery. We compared the two groups for perioperative parameters, adverse events, and the response to NAC. Results The two- and three-course groups showed similar completion rates and overall NAC dose reductions. Although the two-course group showed significantly lower overall grades 3–4 leukopenia and anemia compared to the three-course group, the two groups had similar overall toxicity rates. Postoperative complications were not significantly different between the two groups, except arrhythmia (13 vs . 0%, P  = 0.0007). Only two postoperative in-hospital deaths occurred in the three-course group, due to sepsis following severe pneumonia. Compared to the two-course group, the three-course group was associated with a significantly better clinical response (42.9 vs. 65.2%, P  = 0.0027) and a relatively higher rate of pathological complete response (9.1 vs. 15.3%, P  = 0.212). Conclusion Both two- and three-course DCF regimens in the NAC setting seemed to be equally feasible in locally advanced ESCC patients. Additional DCF courses led to a better NAC response without increasing the incidence of adverse events or postoperative morbidity. Clinical Trial Registration University Hospital Medical Information Network Clinical Trials Registry of Japan (Identification Number UMIN 000015788).